Recent findings from our group point to substantial abnormalities affecting the extracellular matrix (ECM) in medial temporal regions of subjects with schizophrenia, but not bipolar disorder. Our data points to anomalous expression of chondroitin sulfate proteoglycans (CSPGs), a main component of the ECM, in glial cells and ECM. CSPG functions during development and adulthod, such as regulation of neuronal migration, axon outgrowth, stabilization of synaptic connectivity, maintenance of neuronal networks and neuronal microenvironment, bear direct relevance to the pathophysiology of schizophrenia. Preliminary results suggest that similar abnormalities occur in the olfactory epithelium (OE) and olfactory bulb (OB), as well as peripherally in skin fibroblasts, of subjects with SZ. Investigations on ECM abnormalities in the olfactory system (OE and OB), as proposed here, offer compelling advantages. First, neurodevelopmental functions such as neuron diferentiation, migration in OE, and axon outgrowth toward OB, occur throughout life, alongside adult neural functions, making the olfactory system ideally suited for investigations on CSPGs. Second, growing evidence for olfactory deficits in SZ, particularly in association with negative symptoms, renders investigations on the olfactory system directly relevant to the clinical manifestations of this disease. Third, the OE is the only central nervous system structure easily accessible by biopsy, from which cel cultures can be developed. The main goal of these studies is to investigate the relationship between the pathophysiology of CSPG abnormalities in schizophrenia and clinical manifestations of this disease. The potential for CSPG abnormalities to represent a biological marker with pathophysiological relevance and specificity for schizophrenia will be assessed in the context of specific hypotheses on the mechanisms of ECM abnormalities and their association with core symptoms of this disease. The main hypothesis tested is that ECM abnormalities, due to a disruption of molecular pathways regulating CSPG synthesis and secreti0n, affect the olfactory system in subjects with SZ and can be detected peripherally. We postulate that such abnormalities may be associated with specific olfactory deficits and negative symptoms. To test this hypothesis, CSPG abnormalities will be assessed in OE and skin fibroblasts (biopsy/in vitro), as well as the OB (postmortem), from two cohorts of normal control, SZ and BD subjects. Human fibroblast and OE primary cultures obtained from skin and OE biopsies, respectively, will be used to test, in vitro, diagnosis effects on the molecular mechanisms regulating CSPG expression. Biopsy donors will be tested for olfactory functions and on psychiatric rating scales. BD subjects will be included to test whether CSPG abnormalities are specific to SZ or represent a shared feature among major psychoses. PUBLIC HEALTH RELEVANCE: The relevance of the proposed studies resides in their contribution to the understanding of the pathophysiological mechanisms of extracellular matrix abnormalities in schizophrenia and their relationships to the clinical manifestations of this disease. Investigations on neural and non-neural tissues accessible by biopsy will allow us to assess the potential validity of these abnormalities as clinically and pathophysiologically relevant biomarkers for schizophrenia.